Rheumatoid arthritis progression mediated by activated synovial fibroblasts

Neumann, Elena; Lefèvre, Stephanie; Zimmermann, Birgit; Müller‐Ladner, Ulf

doi:10.1016/j.molmed.2010.07.004

Cited by 322 publications

(245 citation statements)

References 87 publications

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“…A combination of genetic predisposition, immunological deregulation and environmental factors contribute to its pathogenesis [1]. The most recognized environmental risk factor for the development and severity of RA is cigarette smoking [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNF, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA. KEY MESSAGES: SIRT1 is upregulated by TNF but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF. AbstractRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study we investigated the regulation, expression and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract.Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF, but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can t...

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Section: Introductionmentioning

confidence: 99%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

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“…These cells respond to cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α through the activation of multiple intracellular signaling pathways, including the mitogenactivated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK), c-Jun NH 2 -terminal kinase (JNK) and p38, and the nuclear factor (NF)-κB system (2,4). Activation of these pathways may result in exaggerated proliferation and expression of multiple cytokines including IL-1β (5-7), and TNFα (6,7,9), as well as the secretion of matrix metalloproteinases (MMPs), which contribute to tissue destruction in RA (1)(2)(3). In addition, Akt activation prevents apoptosis and promotes cell survival of RSFs (10), and the level of phosphorylated (P)-Akt activity is increased by stimulation of primary RSFs with TNFα (10).…”

Section: Introductionmentioning

confidence: 99%

Activated Protein C Inhibits Proliferation and Tumor Necrosis Factor α-Stimulated Activation of p38, c-Jun NH2-Terminal Kinase (JNK) and Akt in Rheumatoid Synovial Fibroblasts

Julovi

Shen

McKelvey

et al. 2013

Mol Med

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Synovial fibroblast proliferation is a hallmark of the invasive pannus in the rheumatoid joint. Activated protein C (APC) is a natural anticoagulant that exerts antiinflammatory and cyto-protective effects in various diseases via endothelial protein C receptor (EPCR) and proteinase-activated receptor (PAR)-mediated pathways. In this study, we investigated the effect and the underlying cellular signaling mechanisms of APC on proliferation of human rheumatoid synovial fibroblasts (RSFs). We found that APC stimulated proliferation of mouse dermal fibroblasts (MDFs) and normal human dermal fibroblasts (HDFs) by up to 60%, but robustly downregulated proliferation of RSFs. APC induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) and enhanced expression of p21 and p27 in a dose-dependent manner in RSFs. The latter effect was inhibited by pretreatment with the ERK inhibitors PD98059 and U0126 but not by p38 inhibitor SB203580. In addition, APC significantly downregulated tumor necrosis factor (TNF)α-stimulated cell proliferation and activation of p38, c-Jun NH 2 -terminal kinase (JNK) and Akt in RSFs. These results provide the first evidence that APC selectively inhibits proliferation and the inflammatory signaling pathways of RSFs. Thus, APC may reduce synovial hyperplasia and pannus invasion in rheumatoid arthritis.

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“…Synovial hyperplasia is characteristic feature of rheumatoid arthritis [27,35] and synovial membrane may be even recognised as the primary pathogenetic site in this disease [15].…”

Section: Pathologymentioning

confidence: 99%